Aggregation prone regions in human proteome: Insights from large‐scale data analyses

Abstract

Protein aggregation leads to several burdensome human maladies, but a molecular level understanding of how human proteome has tackled the threat of aggregation is currently lacking. In this work, we survey the human proteome for incidence of aggregation prone regions (APRs), by using sequences of experimentally validated amyloid-fibril forming peptides and via computational predictions. While approximately 30 human proteins are currently known to be amyloidogenic, we found that 260 proteins (∼1% of human proteome) contain at least one experimentally validated amyloid-fibril forming segment. Computer predictions suggest that more than 80% of the human proteins contain at least one potential APR and approximately two-thirds (65%) contain two or more APRs; spanning 3-5% of their sequences. Sequence randomizations show that this apparently high incidence of APRs has been actually significantly reduced by unique amino acid composition and sequence patterning of human proteins. The human proteome has utilized a wide repertoire of sequence-structural optimization strategies, most of them already known, to minimize deleterious consequences due to the presence of APRs while simultaneously taking advantage of their order promoting properties. This survey also found that APRs tend to be located near the active and ligand binding sites in human proteins, but not near the post translational modification sites. The APRs in human proteins are also preferentially found at heterotypic interfaces rather than homotypic ones. Interestingly, this survey reveals that APRs play multiple, often opposing, roles in the human protein sequence-structure-function relationships. Insights gained from this work have several interesting implications towards novel drug discovery and development. Proteins 2017; 85:1099-1118. © 2017 Wiley Periodicals, Inc.

Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

“…through protein-protein interactions. The few solvent-exposed APRs in native proteins are generally APRs contributing to protein interaction interfaces or catalytic sites ( Ventura et al, 2002 ; Prabakaran et al, 2017 ). Since most APRs are buried, they represent a danger for aggregation only in situations where proteins are partially or completely unfolded, such as during protein translation or translocation, under situations of physiological stress or due to mutations that destabilize the native conformation ( Ganesan et al, 2016 ; Langenberg et al, 2020 ).…”

Effect of charged mutation on aggregation of a pentapeptide: Insights from molecular dynamics simulations

“…52,53 The inhibitory effect is usually attributed to the increased solutesolvent interactions through hydrophilic interactions and reduced solute-solute interactions due to electrostatic repulsion between charged-residues. 53 Our analysis of these gatekeeper flanked-peptide systems (Pep5 to pep8) highlights the complexity and sequencedependence of roles played by the gatekeeper residues to mitigating aggregation. At the end of 50 ns simulation of n 50 concentrated systems, Pep5 (ACE-QSPVLVIYDDT-NME) peptides did not form any aggregates (≥25 copies), in comparison 89% of the Pep1 (ACE-VLVIY-NME) peptides formed large aggregates (Table 2).…”

“…These observations are as expected and fit the accepted view in literature. 15,[52][53][54][55] On the contrary, Pep6 (ACE-QSPKLVIYDDT-NME) system showed greater aggregation propensity than Pep 2 (ACE-KLVIY-NME), with 32.9% and 99.6% of the peptides forming aggregates of 25 or more copies, at the end 50 ns simulation of n 50 and n 105 systems, respectively (Table 2). respectively.…”

Amyloids of multiple species: are they helpful in survival?

“…Proteins are at a continuous risk of aggregation due to several endogenous and exogenous biochemical factors. Particular structural arrangements of residues and motifs may lead to the aggregation of such proteins (Sarkar & Dubey, ; Prabakaran et al, ). Intrinsically disordered proteins and amyloids with functional roles in cellular physiology can further enhance the diversity of the structural–functional paradigm of the proteins (Dunker et al, ; Fowler et al, ).…”